p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells

Abstract

Current therapy for advanced prostate cancer is largely based on androgen deprivation and is mostly palliative because all patients eventually relapse with androgen-independent disease. Doxorubicin (Dx), an anthracycline used commonly as a chemotherapeutic agent in relapsed prostate cancer, is a strong inducer of p53 expression and p21(CIP1/WAF1) (p21) transactivation. Previous reports suggest that p21 may have a role in the modulation to chemotherapy-induced apoptosis, prostate cancer progression and androgen regulation. In order to investigate if p21 has a pro-survival role in the response of prostate cancer cells to cellular stress, we exposed two androgen-regulated human prostate cancer cell lines (MDA PCa 2b and LNCaP) to Dx and growth factor withdrawal. We then studied expression of p53 and p21, cell-cycle kinetics and apoptosis. We have found that p53 protein accumulated in a dose- and time-dependent manner after Dx treatment, while p21 expression increased over time with low but decreased with high Dx doses. Apoptosis occurred in parallel with p21 down-modulation. Dx treatment of p53 knockout cells demonstrated that p21 induction was strictly p53 dependent. Reduction of p21 levels in prostate cancer cells with an antisense p21 adenovirus resulted in sensitization to Dx and accelerated onset of apoptosis in response to growth factor withdrawal. The evidence presented here also suggests that caspase activation mediates the apoptosis in this system and supports that p21 may modulate the threshold of apoptosis in prostate cancer. These observations may thus provide implications onto the integration of chemotherapy and androgen ablation.

p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells

“…The mechanisms leading to cell cycle arrest or apoptosis in response to Adriamycin-induced DNA damage are not well understood, but there is recent evidence showing that in human cancer cells, p21 exhibits inhibitory effects on wt p53-dependent apoptosis induced by low concentrations of ADR [43]. In this study, ADR treatment at quite low doses dramatically elevated p21 and Bax mRNA expression in 213Q/mock cells, but this did not significantly influence their cell viability; thus, it is reasonable to speculate that p21 may block the wt p53-mediated loss of cell viability in 213Q/mock cells with a low degree of DNA damage.…”

Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines

“…Human papilloma virus-E6, a well-known p53 abrogator, was reported to enhance cytotoxicity of CDDP in HCT116 colon cancer cells and MCF-7 breast cancer cells, which retained wild-type p53 (Weller, 1998). Furthermore, in p53 wild-type prostate cancer cell lines including LNCap, it was reported that downregulation of p21 by antisense oligonucleotide enhanced doxorubicin-induced apoptosis (Martinez et al, 2002). These findings indicated that induction of p53/p21 by CDDP suppressed the apoptotic process, and were consistent with our main results that dicoumarol enhanced cytotoxicity of CDDP through suppression of p53/p21 in urogenital cancer cells.…”

Depletion of Endogenous Nitric Oxide Enhances Cisplatin-induced Apoptosis in a p53-dependent Manner in Melanoma Cell Lines

“…Numerous studies have highlighted the ability of p21 to protect glioblastomas, gliomas, colon carcinomas, prostate cancer (14), and melanomas from apoptosis-inducing stimuli. p21 was also found to be overexpressed and is rarely mutated in melanoma (54,63).…”

“…For instance, inhibition of p21 by antisense technology sensitized glioblastoma cells to chemotherapeutic agents (11) and to radiation therapy (12). p21 also appears to protect human colon carcinoma cells and prostate cancer cells against apoptosis (13,14). Additionally, there is evidence that p21 may protect against p53-mediated apoptosis in human melanoma cells (15).…”